Multiple myeloma is a lymphoproliferative disorder involving the B cells/plasma cells of individuals primarily over the age of 40. It is a tumor which almost invariably leads to extensive bony destruction of red marrow areas (particularly the spine, ribs and skull). The cellular and biochemical mechanisms of this bony destruction are still not understood. Clarification of this process could have significant bearing on the chemotherapeutic approach to the treatment of these lesions. This proposal, through the use of animal and human material, specifically seeks to (1) determine the cellular mechanism of bone resorption in multiple myeloma (i.e. define the resorptive roles of osteoclasts, inflammatory cells and tumor cells), (2) determine the relative importance of specific bone destruction and/or the interference of the flow of calcium between bone and plasma pools in the development of myeloma-induced hypercalcemia, (3) determine the effects of specific chemotherapeutic agents (e.g. mithramycin, cyclophosphamide and diphophonates) on normal and myelomatous bone and (4) develop an in vitro assay for specific myeloma cell bone resorptive activity. Bony lesions will be induced in the animal model by I.V. injection of several transplantable mouse plasmacytomas in BALB/c mice. Bone resorption will be studied through radiological monitoring of the skeleton, serum calcium measurements and morphometric analyses of histological bone samples. Lysosomal enzyme histochemical and immunohistochemical techniques will be used selectively stain osteoclasts, macrophages and myeloma cells. The relative % of each cell type will be counted and correlated with serum calcium levels and the morphological quantitation of bone destruction. Radioisotopically-labelled, sterilized bone fragments will be exposed to cultured mouse and human myeloma cells in vitro to assess the bone resorbing capacity of these tumor cells. any therapeutic effects of drug administration will be compared to their effects on normal bone metabolism. The long-term objective of this study is the development of a rational treatment of the skeletal destruction associated with human myeloma.